tbuckley/cabot-search huggingface dataset:
Abstract 2372: Does the ubiquitin E3 ligase glycoprotein 78 (gp78/amfr) link socioeconomic factors, race, and biology in breast cancer? 
Authors: Myles A. Ellis
Journal: Cancer Research (2023)

Abstract This year there will be 260,00 new cases of breast cancer in the United States. Close to 40,000 women living with breast cancer, will die from the disease by the years end. However, these statistics are not evenly distributed across our citizens. Women of Western African descent are 40% more likely to die from breast cancer than their European counterparts. Although socioeconomic factors along with racism, including affordable quality health care, availability of healthy foods, wage gaps, and trustworthiness of our physicians, have a considerable role in the difference in survival, there still is a significant gap in our understanding of the contribution of biology. Therefore, biomarkers, mechanisms, and pathways connected with more aggressive biology that differ by race and genetic ancestry must be examined. The ubiquitin E3 ligase, glycoprotein 78 (GP78/AMFR) is an endoplasmic reticulum-resident protein that degrades unfolded proteins found in the cell. It also supports lipid synthesis, autophagy and targets certain proteins that cause endoplasmic reticulum stress that could result in apoptosis. We have found that GP78 is a functional biomarker for breast cancer in women. Higher levels of this gp78, detected by validated antibody, is associated with more aggressive subtypes of breast cancer (e.g., luminal B, HER2 and triple-negative breast cancer, TNBC) and is expressed at notably elevated levels in breast cancer compared to normal glands. In addition, its expression is associated with poor survival, regardless of subtype, specifically in women of Western African descent. In vivo experiments using murine syngeneic allograft models, comparing wild type and gp78 knock breast cancer cells show the gp78 is required for tumor growth. Further analysis reveals a role for gp78 lipogenesis linked to immune suppression in the tumor microenvironment. Conclusion: These observations suggest a role for gp78 in 1) tumor growth and 2) immune suppression, and implies a role for race and genetic ancestry in the association between gp78 and breast cancer survival. Therefore, corroborating a role for gp78 in both tumor growth and suppression of the tumor immune microenvironment will be an important future goal. We will validate and extend these findings in additional diverse patient populations to define the association between GP78, patient tumor biology, clinical feature, patient exposures, and other social determinants of health. Citation Format: Myles A. Ellis. Does the ubiquitin E3 ligase glycoprotein 78 (gp78/amfr) link socioeconomic factors, race, and biology in breast cancer? [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2372.
Abstract 554: The role of <i>Mycobacterium w</i> as a novel treatment for osteosarcoma
Authors: Kirsten Stefan, Arpit Dheeraj, Dhanir Tailor, Sushil Kumar, Wenqi Li, Rajiv Modi, Manjul Joshipura, Bakulesh Khamar, Lara E. Davis, Sanjay V. Malhotra
Journal: Cancer Research (2023)

Abstract Osteosarcoma (OS) is the most common malignant primary tumor of bone and occurs in adolescents and young adults as well as in the elderly. Despite a number of large clinical trial efforts, metastatic sarcoma remains a lethal disease, and there have been no meaningful advances in therapy or improvements in patient outcomes for decades. Mycobacterium w (Mw, also known as Mycobacterium indicus pranii) is a non-pathogenic strain of mycobacterium which has been used as an immunomodulator against leprosy, tuberculosis and several cancers and is approved for treatment of NSCLC along with chemotherapy in India. Mw promotes a Th1 immune response and its administration in tumor bearing animals is associated with an increase in total number of tumor infiltrating immune cells (TIIC) with decrease in FOXP3 and PD-1 expressing TIIC in pancreatic cancer and melanoma. Previous studies in our lab have shown that Mw promotes mature dendritic cell and activated CD8+ T cell accumulation within the tumor microenvironment in a mouse model of pancreatic cancer. We compared the effects Mw with standard of care doxorubicin on OS tumor progression in a subcutaneous K7M2 syngeneic mouse model. Mw treatment was more effective at tumor inhibition than doxorubicin. Immunohistochemistry analyses of OS tumors revealed an increase in macrophages following Mw treatment. We aim to further analyze the tumor immune microenvironment using a panel of 28 antibodies to determine alterations due to Mw treatment. With these results we hope to show that Mw is a promising candidate for further development as a therapy for OS. Citation Format: Kirsten Stefan, Arpit Dheeraj, Dhanir Tailor, Sushil Kumar, Wenqi Li, Rajiv Modi, Manjul Joshipura, Bakulesh Khamar, Lara E. Davis, Sanjay V. Malhotra. The role of Mycobacterium w as a novel treatment for osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 554.
Abstract 2692: The combination of ulixertinib (ERK1/2 Inhibitor) and KRASG12C inhibition demonstrates significant efficacy in preclinical models
Authors: Deborah Knoerzer, Anupama Reddy, Jessica A. Box, Anna Groover, Brent Kreider, Martin Teresk, Caroline M. Emery
Journal: Cancer Research (2023)

Abstract Ulixertinib (BVD-523) is a first-in-class and best-in-class small molecule inhibitor of ERK1/2 currently being investigated in several oncology clinical trials, both as a single agent and in combination with other therapeutics. Ulixertinib has demonstrated efficacy in patients with tumors harboring alterations within the RAS-MAPK pathway. KRAS is the most frequently mutated oncogene in cancer and is a key mediator of the RAS-MAPK signaling pathway resulting in proliferation and cellular growth. The specific KRASG12C mutation occurs in approximately 10% of non-small cell lung cancer (NSCLC), 3% of colorectal cancer, and 1-2% across all other tumor types. KRASG12C mutant-inhibitors, including AMG-510 (sotorasib), MRTX849 (adagrasib), and JDQ443 have demonstrated efficacy in KRASG12C-mutant cancers, including NSCLC. Clinically described mechanisms of acquired resistance to KRASG12C inhibitors converge on reactivation of the RAS-MAPK pathway. We hypothesized combining ulixertinib with a KRASG12C inhibitor would circumvent resistance to single agent KRASG12C inhibition, generating increased magnitude and duration of response compared to either single agent alone. The efficacy of ERK1/2 inhibitor, ulixertinib, in combination with KRASG12C inhibitor, adagrasib, was assessed in cell line derived xenograft models harboring KRASG12C mutations. Models were selected based on response to single agent adagrasib, ranging from sensitive to partially responsive. Combination treatment resulted in superior tumor growth inhibition compared to dosing of either single agent. RNA sequencing was performed on tumor samples that were collected 2 hours after the last dose of treatment. Expression of the mutant KRAS alleles were readily confirmed from RNA sequencing data in all models. Gene expression analysis showed differential expression of MAPK pathway genes in monotherapy versus combination therapy treated groups. In summary, ulixertinib combined with adagrasib exhibited robust pre-clinical activity in a variety of xenograft models with KRASG12C and should be further evaluated. Citation Format: Deborah Knoerzer, Anupama Reddy, Jessica A. Box, Anna Groover, Brent Kreider, Martin Teresk, Caroline M. Emery. The combination of ulixertinib (ERK1/2 Inhibitor) and KRASG12C inhibition demonstrates significant efficacy in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2692.
Abstract 3727: Development of a new All-In-One inducible lentiviral shRNA/gRNA Vector
Authors: Lipeng Wu, Hua Su, Justin Fellows, Mao Fu, Julian Heller, Brian Park, Dezhong Yin
Journal: Cancer Research (2023)

Abstract Tet-On is a powerful inducible system and a classical tool to regulate gene expression in mammalian cells. It has also been applied to regulate Pol III-driven transcription, such as shRNA or gRNA driven by a U6 or H1 promoter. However, all of the current versions of Tet-On shRNA vectors are based on H1-2O2 or U6-2O2 promoters, which are only compatible with first-generation tetracycline repressor TetR. In addition, these promoters have the problem of driving downstream transcription without the binding of the Tet regulatory protein. Here, we developed a new system that is built upon tetracycline activator protein, Tet-On 3G, combined with a new structure of Tet responsive promoter H1-4O4, which tightly regulates the downstream transcription of gRNA or shRNA. The responsiveness of our system to Doxycycline regulation is dramatically improved compared with the current versions. The new Tet-On system is further optimized into a compact structure to be compatible with the lentivirus package (All-In-One Lenti-Tet-On system), which still keeps the leaky expression at an undetectable level. Combined with all these features, the new generation of the Tet-On system offers broad applications in gene knocking down and genomic editing. Citation Format: Lipeng Wu, Hua Su, Justin Fellows, Mao Fu, Julian Heller, Brian Park, Dezhong Yin. Development of a new All-In-One inducible lentiviral shRNA/gRNA Vector. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3727.
Abstract 6590: Undergraduate e-mentoring in cancer research: The ACE scholars program
Authors: Cristina Baciu, Compton Zachary, Carlo Maley
Journal: Cancer Research (2023)

Abstract Only 1 in 4 undergraduate college students report having had access to mentoring while in college. To create community and training opportunities for a diverse body of undergraduate students (incl. online students) interested in cancer research, we developed a well-rounded e-mentoring program that incorporates alternated sessions of scientific mentoring (i.e., design a study, create a poster) and professional development (i.e., graduate school strategy and applications, networking). The theoretical background of our program derives from project and team-based learning, which state that students tend to learn better and be more engaged when working hands-on on a given project, in teams. Our teams are led by experienced undergraduate researchers, which enables them to gain leadership experience before applying to graduate school. We implemented this e-mentoring program in a research center at a large southwestern public university, where 43 undergraduate research assistants were mentored via Zoom during the Spring of 2022. At the end of the semester, we administered a survey to assess program effectiveness and collect student feedback. 31 students took the survey, which revealed that during Spring 2022, 25% of students were responsible for the care of children or other family member(s), 47% worked part-time and 22% worked full-time, and 56% of students encountered personal and/or professional challenges. Furthermore, we measured program effectiveness using the College Student Mentoring Scale, a comprehensive tool that measures students’ perceived psychological and emotional support, degree and career support, academic knowledge support, and role modeling they received during their time in the program. Findings indicate that 82% of students felt they received psychological and emotional support and degree and career support while in the program. Moreover, 96.3% of students indicated that they felt they received academic knowledge support and benefited from role modeling while in the ACE Scholars Program. Additionally, 85% of students agreed or strongly agreed that the ACE Scholars Program, with its research experience and career and professional development components, has helped them be prepared for their future endeavors. Overall, 86% of the students indicated that they were extremely satisfied with the ACE Scholars Program. We will discuss the implications of this program and its findings for the practice of e-mentoring undergraduate students who are interested in cancer research. Citation Format: Cristina Baciu, Compton Zachary, Carlo Maley. Undergraduate e-mentoring in cancer research: The ACE scholars program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6590.
Abstract 3968: Conophylline-target ARL6ip1 regulates Ran-mediated cellular migration and invasion in human colorectal cancer cells
Authors: Yinzhi Lin, Sivasundaram Karnan, Hideaki Ito, Kazuo Umezawa
Journal: Cancer Research (2023)

Abstract Introduction: Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla. We isolated conophylline as an inhibitor of K-Ras functions. It is known to ameliorate various disease models in animals, including cancer, diabetes mellitus, NASH, and hepatic cirrhosis. On the other hand, its molecular target was determined to be ADP-ribosylation factor-like 6-interacting protein 1 (ARL6ip1) using a conophylline-biotin conjugate. ARL6ip1 is located in the endoplasmic reticulum (ER) membrane, and the conophylline-binding domain was determined by deletion mutation analysis. Known functions of ARL6ip1 include inhibition of apoptosis, inhibition of glutamate transporter, and modulation of the ER structure. However, whether ARL6ip1 is involved in the mechanisms of various biological activities of conophylline has not been proven, since knockdown of ARL6ip1 has often failed to change the cellular phenotypes. Therefore, in the present research, we knocked out ARL6ip1 in human colon carcinoma cells by CRISPR-Cas9 and studied the involvement and mechanism of ARL6ip1 in the anticancer activity of conophylline. Ran activity was measured by a pull-down assay with Ran-GTP antibody. Materials and Methods: Conophylline was isolated from the leaves of Ervatamia microphylla. We employed HCT116 and DLD1 cells as human colorectal cancer cells. Tumorigenicity was measured by soft agar colony formation. Cellular migration was measured by a wound healing assay and cell tracking analysis. Cellular invasion was measured by a Matrigel chamber assay. Results: Conophylline inhibited soft agar colony formation in HCT116 and DLD1 cells. It inhibited migration and invasion in HCT116 and DLD1 cells at nontoxic concentrations. Knockout of ARL6ip1 also decreased tumorigenicity, migration, and invasion in HCT116 and DLD1 cells. The mechanistic study was carried out with HCT116 cells. ARL6 and Ran are both G-proteins and are reported to interact with ARL6ip1. Although knockdown of ARL6 did not change the cell migratory activity, knockdown of Ran inhibited the migration. Conophylline inhibited the interaction of ARL6ip1 to Ran in the proximity ligation assay. Moreover, conophylline inhibited the Ran activity. Conclusion: CRISPR-Cas9 knockout of ARL6ip1 showed a similar anticancer activity as treatment with conophylline. It is likely that the anticancer activity of conophylline would be mediated by the ARL6ip1-Ran system. Thus, ARL6ip1 would be a useful molecular target for the treatment of cancer. Citation Format: Yinzhi Lin, Sivasundaram Karnan, Hideaki Ito, Kazuo Umezawa. Conophylline-target ARL6ip1 regulates Ran-mediated cellular migration and invasion in human colorectal cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3968.
Abstract 5841: Exploring the role of versican in immune exclusion within triple negative breast cancer
Authors: Priyanka Hirani, Kimberly M. Alonge, Daniel J. Pennington, Pedro R. Cutillas, Thomas N. Wight, Oliver M. Pearce
Journal: Cancer Research (2023)

Abstract Immunotherapy has found limited success in solid tumors such as triple negative breast cancer (TNBC). The poor response can be attributed to the presence of the extracellular matrix (ECM) that can act biochemically or physically to interfere with cytotoxic T cell migration, leading to a limitation in tumor cell killing. Through previous work on deconstructing this matrix and outlining the spatial arrangement of proteins, we were able to identify versican as a key protein in T cell location. Versican is a chondroitin sulfate proteoglycan and has multiple functions in the ECM due to its ability to bind many ECM components. Using immunohistochemistry in this study, we analyzed the localization of CD8+ T cells within human TNBC tissues to classify them as inflamed (tumorhi, stromahi), desert (tumorlo, stromalo) or immune excluded (tumorlo, stromahi). From the analysis of 26 tissues, nearly half were classified as immune excluded with most of the CD8+ T cells restricted to the stroma, whilst only a quarter were inflamed. When comparing this to versican accumulation we noticed that immune excluded tissues have significantly higher levels of versican in the tumor epithelium compared to inflamed tissues where versican is mostly found within the stroma. To investigate the function of versican’s structure, we carried out transwell migration assays using versican enriched protein treated with or without chondroitinase ABC and showed that the chondroitin sulfates attached to versican’s peptide backbone are an important factor towards T cell trafficking with a reduction in migration following chondroitinase ABC treatment. Comparison of versican levels to chondroitin sulfate via immunohistochemistry showed a positive correlation within inflamed tissues, however no correlation was observed in immune excluded tissues. Versican isoforms expression in TNBC tissues and cell lines was examined with qRT-PCR which showed that within all tissues and cell lines the V0 and V1 isoform are the highest expressed out of the 5 isoforms. Overall, in this work, we have found that versican is differentially expressed in excluded tissues in comparison to inflamed tissues. With chondroitin sulfate shown to play a major role in immune cell trafficking, understanding how it differs between inflamed and excluded tumors can help identify potential targets to improve immunotherapy response. Citation Format: Priyanka Hirani, Kimberly M. Alonge, Daniel J. Pennington, Pedro R. Cutillas, Thomas N. Wight, Oliver M. Pearce. Exploring the role of versican in immune exclusion within triple negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5841.
Abstract 5875: Rab37 mediates intracellular trafficking and membrane presentation of PD-1 in T cells to foster an immunosuppressive microenvironment in lung cancer
Authors: Wan-Ting Kuo, I-Ying Kuo, Shih-Ting Wu, Wu-Chou Su, Yi-Ching Wang
Journal: Cancer Research (2023)

Abstract Programmed cell death protein 1 (PD-1) expressed on the surface of CD8+ T cells is known as an immune checkpoint protein. High expression of PD-1 leads to T-cell dysfunction in the tumor microenvironment (TME). Our published studies show that Rab37 small GTPase-mediated vesicular trafficking of cell surface proteins and cytokines is critical in immunosuppressive TME. Here, we identify novel mechanisms of intracellular trafficking and plasma membrane presentation of PD-1 mediated by Rab37. Confocal immunofluorescence (IF) and vesicles isolation data demonstrated that PD-1 colocalized with Rab37-specific vesicles in T cells in a GTP-dependent manner. Total internal reflection fluorescence imaging, membrane fractionation, and flow cytometric analyses confirmed the dynamic trafficking and membrane presentation of PD-1 by Rab37. In addition, sucrose density gradient centrifugation and IF revealed that the level of glycosylated wild-type PD-1 in membrane compartment was more than glycosylation mutant PD-1, suggesting that glycosylation mutant PD-1 delayed in recruitment to the Rab37 vesicles and thus stalled in membrane presentation. Furthermore, T cell proliferation and activity were downregulated in Rab37 wild-type splenocytes co-cultured with cancer cells compared to those from Rab37 knockout mice using various T cell functional assays. Clinically, the multiplex IF-immunohistochemical assay indicated that the tumor infiltrated Rab37+/PD1+/TIM-3+/CD8+ exhaustion T cells were more in late staged lung cancer patients compared to those in early staged patients. Importantly, patients with Rab37+/PD-1+/TIM-3+/CD8+ tumor infiltrated T cells expression profile correlated with poor overall survival. Our results provide first trafficking mode of PD-1 mediated by Rab37 small GTPase and novel evidence of the tumor promoting function of Rab37/PD-1 axis in T cells of the tumor microenvironment. Citation Format: Wan-Ting Kuo, I-Ying Kuo, Shih-Ting Wu, Wu-Chou Su, Yi-Ching Wang. Rab37 mediates intracellular trafficking and membrane presentation of PD-1 in T cells to foster an immunosuppressive microenvironment in lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5875.